Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
J Immunol. 2011 Aug 15;187(4):2015-22. doi: 10.4049/jimmunol.1100713. Epub 2011 Jul 8.
Monoclonal anti-CD3 Abs have been used clinically for two decades to reverse steroid-resistant acute graft rejection. In autoimmune diabetes, short course treatment with FcR-nonbinding (FNB) anti-CD3 mAb in mice with recent onset of diabetes induces long-term disease remission. Induction of tolerogenic regulatory T cells (Tregs) has been implicated to be one of the mechanisms of action by FNB anti-CD3 mAb in these settings. In this study, we examined the effect of FNB anti-CD3 mAb treatment on the homeostasis of naive, effector, and regulatory T cells in vivo. Anti-CD3 treatment induced a transient systemic rise in the percentage but not absolute number of CD4(+)Foxp3(+) Tregs due to selective depletion of CD4(+)Foxp3(-) conventional T cells. T cell depletion induced by FNB anti-CD3 mAb was independent of the proapoptotic proteins Fas, caspase-3, and Bim and was not inhibited by overexpression of the anti-apoptotic protein, Bcl-2. Tregs were not preferentially expanded and we found no evidence of conversion of conventional T cells into Tregs, suggesting that the pre-existing Tregs are resistant to anti-CD3-induced cell death. Interestingly, expression of the transcription factor Helios, which is expressed by thymus-derived natural Tregs, was increased in Tregs after FNB anti-CD3 mAb treatment, suggesting that the anti-CD3 treatment can alter, and potentially stabilize, Treg function. Taken together, the results suggest that FNB anti-CD3 therapy promotes tolerance by restoring the balance between pathogenic and regulatory T cells.
单克隆抗 CD3 Abs 已被临床使用了二十年，用于逆转类固醇耐药的急性移植物排斥反应。在自身免疫性糖尿病中，早期发病的糖尿病小鼠接受 FcR 非结合（FNB）抗 CD3 mAb 的短期疗程治疗，可诱导长期疾病缓解。诱导免疫耐受的调节性 T 细胞（Tregs）被认为是 FNB 抗 CD3 mAb 在这些情况下的作用机制之一。在这项研究中，我们研究了 FNB 抗 CD3 mAb 治疗对体内幼稚、效应和调节性 T 细胞稳态的影响。抗 CD3 治疗导致 CD4(+)Foxp3(+)Tregs 的百分比而非绝对数量的短暂性全身性增加，这是由于 CD4(+)Foxp3(-)常规 T 细胞的选择性耗竭。FNB 抗 CD3 mAb 诱导的 T 细胞耗竭与促凋亡蛋白 Fas、caspase-3 和 Bim 无关，并且不受抗凋亡蛋白 Bcl-2 过表达的抑制。Tregs 并未优先扩增，我们也没有发现常规 T 细胞转化为 Tregs 的证据，这表明预先存在的 Tregs 对抗 CD3 诱导的细胞死亡具有抗性。有趣的是，转录因子 Helios 的表达，它由胸腺衍生的天然 Tregs 表达，在 FNB 抗 CD3 mAb 治疗后在 Tregs 中增加，这表明抗 CD3 治疗可以改变并可能稳定 Treg 功能。综上所述，这些结果表明，FNB 抗 CD3 治疗通过恢复致病性和调节性 T 细胞之间的平衡来促进耐受。
